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Research ArticleArticle

Constitutive Androstane Receptor-Mediated Up-Regulation of ATP-Driven Xenobiotic Efflux Transporters at the Blood-Brain Barrier

Xueqian Wang, Destiny B. Sykes and David S. Miller
Molecular Pharmacology September 2010, 78 (3) 376-383; DOI: https://doi.org/10.1124/mol.110.063685
Xueqian Wang
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Destiny B. Sykes
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David S. Miller
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Abstract

ATP-driven efflux transporters at the blood-brain barrier both protect against neurotoxicants and limit drug delivery to the brain. In other barrier and excretory tissues, efflux transporter expression is regulated by certain ligand-activated nuclear receptors. Here we identified constitutive androstane receptor (CAR) as a positive regulator of P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and breast cancer resistance protein (BCRP) expression in rat and mouse brain capillaries. Exposing rat brain capillaries to the CAR activator, phenobarbital (PB), increased the transport activity and protein expression (Western blots) of P-glycoprotein, Mrp2, and BCRP. Induction of transport was abolished by the protein phosphatase 2A inhibitor, OA. Similar effects on transporter activity and expression were found when mouse brain capillaries were exposed to the mouse-specific CAR ligand, 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). In brain capillaries from CAR-null mice, TCPOBOP did not increase transporter activity. Finally, treating mice with 0.33 mg/kg TCPOBOP or rats with 80 mg/kg PB increased P-glycoprotein-, Mrp2-, and BCRP-mediated transport and protein expression in brain capillaries assayed ex vivo. Thus, CAR activation selectively tightens the blood-brain barrier by increasing transport activity and protein expression of three xenobiotic efflux pumps.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.063685.

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    CNS
    central nervous system
    CAR
    constitutive androstane receptor
    PXR
    pregnane X receptor
    PCN
    pregnenolone 16α-carbonitrile
    TCPOBOP
    1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene
    NBD-CSA
    [N-°(4-nitrobenzofurazan-7-yl)-d-Lys8]-cyclosporine A
    Mrp
    multidrug resistance-associated protein
    BCRP
    breast cancer resistance protein
    OA
    okadaic acid
    PB
    phenobarbital
    LTC4
    leukotriene C4
    FTC
    fumitremorgin C
    PP2A
    protein phosphatase 2A
    BSA
    bovine serum albumin
    PBS
    phosphate-buffered saline
    PSC833
    valspodar
    MK571
    3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
    Ko143
    (3S, 6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester.

  • Received January 20, 2010.
  • Accepted June 14, 2010.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 78 (3)
Molecular Pharmacology
Vol. 78, Issue 3
1 Sep 2010
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Research ArticleArticle

Constitutive Androstane Receptor-Mediated Up-Regulation of ATP-Driven Xenobiotic Efflux Transporters at the Blood-Brain Barrier

Xueqian Wang, Destiny B. Sykes and David S. Miller
Molecular Pharmacology September 1, 2010, 78 (3) 376-383; DOI: https://doi.org/10.1124/mol.110.063685

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Research ArticleArticle

Constitutive Androstane Receptor-Mediated Up-Regulation of ATP-Driven Xenobiotic Efflux Transporters at the Blood-Brain Barrier

Xueqian Wang, Destiny B. Sykes and David S. Miller
Molecular Pharmacology September 1, 2010, 78 (3) 376-383; DOI: https://doi.org/10.1124/mol.110.063685
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